Protein secretion is required for pregnancy-associated plasma protein-A to promote lung cancer growth in vivo.
Protein secretion is required for pregnancy-associated plasma protein-A to promote lung cancer growth in vivo.
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DOI：
10.1371/journal.pone.0048799
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ma MZ
中科院分区：
文献类型：
--
作者：
Pan H;Hanada S;Zhao J;Mao L;Ma MZ
据报道，妊娠相关血浆蛋白 A (PAPPA) 通过 IGF 结合蛋白 (IGFBP) 的蛋白水解降解来调节胰岛素样生长因子 (IGF) 信号通路的活性，从而增加受体可用的游离 IGF 的局部浓度。在这项研究中，我们发现 PAPPA 是从所检查的七种肺癌细胞系中的两种分泌的。经测试，永生化正常支气管上皮细胞 (HBE) 均不分泌 PAPPA。这些细胞中 PAPPA 的表达水平和分泌之间没有相关性。过表达PAPPA并伴有分泌的细胞系在体外细胞培养条件下没有表现出明显的增殖变化，但在异种移植模型中表现出体内肿瘤生长的显着增强。相反，过表达PAPPA但不分泌的细胞系在体外和体内均表现出肿瘤生长的减少。通过 RNAi 敲除下调 PAPPA 表达和分泌可降低植入体内后的肿瘤生长。 PAPPA 的肿瘤促进活性似乎主要是通过增强 IGF 信号通路介导的，肿瘤样本中下游 Akt 激酶磷酸化的显着增加表明了这一点。我们的结果表明 PAPPA 分泌可能在肺癌的生长和进展中发挥重要作用。
Pregnancy-associated plasma protein-A (PAPPA) has been reported to regulate the activity of insulin-like growth factor (IGF) signal pathway through proteolytic degradation of IGF binding proteins (IGFBPs) thereby increasing the local concentration of free IGFs available to receptors. In this study we found that PAPPA is secreted from two out of seven lung cancer cell lines examined. None of immortalized normal bronchial epithelial cells (HBE) tested secrets PAPPA. There is no correlation between expression level and secretion of PAPPA in these cells. A cell line over-expressing PAPPA accompanied with secretion shows no notable changes in proliferation under cell culture conditions in vitro, but displays significantly augmentation of tumor growth in vivo in a xenograft model. In contrast, a cell line over-expressing PAPPA without secretion exhibits reduction of tumor growth both in vitro and in vivo. Down-regulation of PAPPA expression and secretion by RNAi knockdown decreases tumor growth after implanted in vivo. The tumor promoting activity of PAPPA appears to be mediated mainly through augmentation of the IGF signaling pathway as indicated by notable increases in downstream Akt kinase phosphorylation in tumor samples. Our results indicate that PAPPA secretion may play an important role in lung cancer growth and progression.
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